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Notch is a large cell-surface receptor that is activated by contact with membrane-bound ligands on neighboring cells. The ligands that activate Notch include Delta and Serrate, and Lag-2 is a Notch ligand in c. elegans. Activation of Notch by binding with its ligand on the surface of neighboring cells is involved in several developmental pathways, helping to determine cell fate. Much of the early insight into Notch signaling was derived from genetic studies in Drosophila and C. elegans models. Three different proteolytic steps process the 300 kD precursor of mature Notch. One protease is a furin-like enzyme that cleaves Notch constitutively adjacent to the amino acid sequence RQRR in the extracellular domain. Another proteolytic step in Notch processing is carried out by TACE, also known as ADAM17. Binding of extracellular ligand to Notch also induces cleavage at the transmembrane region by a gamma-secretase activity that is dependent on presenilin-1. The exact identity of the polypeptide that catalyzes the gamma-secretase enzyme activity has been debated. Labeling of presenilin with irreversible gamma-secretase transition state inhibitors indicates that is itself in fact the site of protease activity (Esler et al. 2000). It has also been argued that the gamma secretase is not presenilin-1 itself, but another polypeptide that requires Notch for its activity and is distinct from Presenilin-1 (Taniguchi et al, 2002). Cleavage of Notch in the extracellular domain releases the Notch intracellular domain (NCID) which migrates into the nucleus where it associates with CSL transcription factors and acts as a transcriptional coactivator. The proteolytic processing of Notch resembles in several ways the proteolytic processing of amyloid presursor protein (APP) that is implicated in plaque formation in Alzheimer’s disease, with TACE and Presenilin-1 implicated in proteolytic processing of both Notch and APP. |
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Bart De Strooper and Wim Annaert. Presenilins and the intramembrane proteolysis of proteins: facts and fiction. Nature Cell Biology. 3:E221-E225(2001)
Esler, W.P. et al. (2000) Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol 2(7), 428-34
Harald Steiner and Christian Haass. Intramembrane Proteolysis by Presenilins. Nature Reviews. Molecular Cell Biology. 1:217-224 (2000).
Logeat, F. et al. (1998) The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A 95(14), 8108-12
Mumm, J.S. et al. (2000) A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5(2), 197-206
Schroeter, E.H., Kisslinger, J.A., Kopan, R. (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393(6683), 382-6
Selkoe, D.J. (2001) Presenilin, Notch, and the genesis and treatment of Alzheimers disease. Proc Natl Acad Sci U S A 98(20):11039-41
Taniguchi, Y. et al. (2002) Notch receptor cleavage depends on but is not directly executed by presenilins. Proc Natl Acad Sci U S A 99(6), 4014-9
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